Iron is a vital element in human metabolism. Due to its unique ability to act both as an electron donor [in its ferrous state] and as an electron acceptor [in its ferric state], iron plays an imperative part in cellular respiration as well as oxygen transport and storage. However, due to its ability to receive and transfer electrons, iron can cause severe oxidative stress and tissue damage [1]. As iron has an essential role in both energy metabolism and damaging potential, its absorption, transfer, and metabolism are tightly regulated. The regulation of iron is done mainly by adjusting absorption [2]. This is due to the fact that the ability of the body to secrete iron is negligible [2].
Iron is also recycled within the body as senescent red blood cells are phagocytosed by reticuloendothelial macrophages and their iron content is either used for hematopoiesis if needed or stored for further use. Regulation of iron metabolism is mediated, mainly, by hepcidin, a small peptide hormone [25 amino acids] which is synthesized and secreted by the liver [3]. Hepcidin prevents iron transport by binding to the iron transporter ferroportin which is located on the basal membrane of enterocytes, reticuloendothelial cells, and hepatocytes. Hepcidin binding causes internalization of ferroportin from the plasma membrane into the cell and its ultimate degradation [4]. As a result, in the presence of hepcidin, iron is not absorbed or recycled from the reticuloendothelial cells and circulating iron levels are reduced. Hepcidin levels are controlled by multiple stimuli including: iron stores [5], hypoxia [6, 7], inflammation [8], and erythropoiesis [9]. Since hepcidin is a small hormone peptide, it is filtered and degraded by the kidney. Hepcidin levels are increased in chronic kidney disease [CKD] and negatively correlated with the glomerular filtration rate [GFR] [10, 11]. The mechanisms responsible for this phenomenon in CKD include a reduced renal clearance, increased inflammatory cytokines, and reduced erythropoietin levels [12-14].
In addition, CKD patients have an absolute iron deficiency. This can arise from an increased rate of blood loss during dialysis [15]. The frequent phlebotomies, and blood remaining in the dialysis tubing, contribute to iron loss [16]. The high rate of iron loss [1–3 g/year] is also due to gastrointestinal bleeding from the combination of gastritis and platelet dysfunction [17]. This is common in both dialysis- and non-dialysis [ND]-dependent CKD [18]. Decreased gastrointestinal iron absorption and malnutrition contribute as well.
Due to the combination of reduced iron absorption and increased iron losses, iron deficiency is common among CKD patients who are both ND and dialysis dependent.
The following 2 forms of iron deficiency are recognized: absolute [true] iron deficiency and functional iron deficiency. Absolute iron deficiency is defined by severely reduced or absent iron stores in bone marrow, liver, and spleen. Functional iron deficiency is defined by normal or increased total body iron stores which are unavailable for incorporation into erythroid precursors for erythropoiesis [19]. Functional iron deficiency is mainly due to increased levels of hepcidin which reduce the ability to recruit iron stores from reticuloendothelial cells and hepatocytes for erythropoiesis.
Outcomes of Iron Deficiency Anemia in CKD
Anemia in CKD has been shown to be associated with an increased risk of morbidity and mortality [20-23]. In a large observational study, 27,998 patients with CKD were followed up for approximately 5.5 years [20]. The authors reported a higher baseline prevalence of anemia in patients who died than in those who survived [as well as a higher prevalence of coronary artery disease, congestive heart failure, and diabetes mellitus]. Furthermore, the increase in the prevalence of anemia over the observation period was greatest in those who died despite a shorter period of observation.
The high rates of heart disease and anemia in those who died suggest that anemia accelerates the progression of heart disease and increases the risk of death. However, anemia may be a marker for severity of CKD rather than a causative factor [20].
A retrospective cohort study among patients with incident CKD who had hemoglobin [Hb] measurements, in a large health maintenance organization administrative data set, evaluated 5,885 patients [24]. Anemia was found to be a predictor of excess mortality, excess cardiovascular hospitalizations, and excess end-stage renal disease [ESRD]. For those with the most severe anemia [Hb